State‐dependent action of grayanotoxin I on Na<sup>+</sup> channels in frog ventricular myocytes

Yuki, Tsunetsugu; Yamaoka, Kaoru; Yakehiro, Masuhide; Seyama, Issei

doi:10.1111/j.1469-7793.2001.00777.x

Cited by 24 publications

(20 citation statements)

References 23 publications

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“…This might explain the difference in binding kinetics between GTX and BTX. BTX dissociates from the open state of the sodium channel (9), whereas GTX exclusively dissociates from the closed state (10). It is supposed that BTX dissociates from its receptor site in the ion-conducting pore and shifts to a cytoplasmic membrane site during the open state of the channel, as if it were reversing its itinerary (9).…”

Section: Discussionmentioning

confidence: 99%

“…Protocol That Derives k on and k off of GTX Binding-In a previous communication, we presented a method that enables us to independently measure rate constants k on and k off for toxin binding and unbinding to sodium channels (10). GTX modifies sodium channels in proportion to the time integral of the unmodified sodium channel conductance (T oNa ; Fig.…”

Section: Comparison Of Thementioning

confidence: 99%

“…2A). Moreover, the GTX action has a unique dependence on the state of the sodium channel; although BTX binds to and dissociates from the channel in its open state (9), GTX binds only to the open channel and dissociates from the closed channel (10).…”

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confidence: 99%

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Distinct Sites Regulating Grayanotoxin Binding and Unbinding to D4S6 of Nav1.4 Sodium Channel as Revealed by Improved Estimation of Toxin Sensitivity

Maejima¹,

Kinoshita²,

Seyama³

et al. 2003

Journal of Biological Chemistry

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Grayanotoxin (GTX) exerts selective effects on voltagedependent sodium channels by eliminating fast sodium inactivation and causing a hyperpolarizing shift in voltage dependence of channel activation. In this study, we adopted a newly developed protocol that provides independent estimates of the binding and unbinding rate constants of GTX (k on and k off ) to GTX sites on the sodium channel protein, important in the molecular analysis of channel modification. Novel GTX sites were determined in D2S6 (Asn-784) and D3S6 (Ser-1276) by means of site-directed mutagenesis; the results suggested that the GTX receptor consists of the S6 transmembrane segments of four homologous domains facing the ion-conducting pore. We systematically introduced at two sites in D4S6 (Na v 1.4-Phe-1579 and Na v 1.4-Tyr-1586) amino acid substituents with residues containing hydrophobic, aromatic, charged, or polar groups. Generally, substitutions at Phe-1579 increased both k on and k off , resulting in no prominent change in dissociation constant (K d ). It seems that the smaller the molecular size of the residue at Na v 1.4-Phe-1579, the larger the rates of k on and k off , indicating that this site acts as a gate regulating access of toxin molecules to a receptor site. Substitutions at Tyr-1586 selectively increased k off but had virtually no effect on k on , thus causing a drastic increase in K d . At position Tyr-1586, a hydrophobic or aromatic amino acid side chain was required to maintain normal sensitivity to GTX. These results suggest that the residue at position Tyr-1586 has a more critical role in mediating GTX binding than the one at position Phe-1579. Here, we propose that the affinity of GTX to Na v 1.4 sodium channels might be regulated by two residues (Phe and Tyr) at positions Phe-1579 and Tyr-1586, which, respectively, control access and binding of GTX to its receptor.

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Section: Discussionmentioning

confidence: 99%

Section: Comparison Of Thementioning

confidence: 99%

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Distinct Sites Regulating Grayanotoxin Binding and Unbinding to D4S6 of Nav1.4 Sodium Channel as Revealed by Improved Estimation of Toxin Sensitivity

Maejima¹,

Kinoshita²,

Seyama³

et al. 2003

Journal of Biological Chemistry

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“…They increase the permeability of sodium (Na + ) ions in the stimulated membranes. The toxin affects the skeletal muscles, the heart muscle, the respiratory system, and the central nervous system (3). The most common signs in mad honey poisoning are significant hypotension and bradycardia (4).…”

Section: Introductionmentioning

confidence: 99%

Pseudocholinesterase Levels Are Not Decreased in Grayanotoxin (Mad Honey) Poisoning in Most Patients

Gunduz¹,

Kalkan²,

Türedi³

et al. 2012

The Journal of Emergency Medicine

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“…Son olarak modifiye Na kanallarının aktivasyon potansiyeli, kanalın hiperpolarizasyonuna neden olur. Uyarılabilir hücreler (sinir ve kas) depolarize durumda kalır (3,15,16) . Bir çay kaşığı balın bile zehirlenmeye neden olabildiği olgular olmakla birlikte, zehirlenme olguların çoğunda tüketilen bal miktarı 5-30 g arasında değişe-bilmektedir, ancak balı tadan herkeste benzer zehirlenme belirtileri olmayabilir (17) .…”

Section: Introductionunclassified

The dose-dependent cardiovascular eﬀects of intravenous grayanotoxin-III in rats

Yılmaz¹,

Kaya²,

Yaykaşlı³

et al. 2017

BUCH

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ÖZAmaç: Deli bal zehirlenmelerin büyük bir kısmı ülkemizde görülmektedir. Deli bal içinde bulunan toksinlerin temel kaynağı Rhododendron türü bitkiler olup, bu bitkilerdeki toksinlerden en fazla grayanotoksin-III bulunur. Deli bal zehirlenmelerinde klinikte bradikardi, atriyoventriküler blok, asistoli, hipotansiyon, salivasyon gibi semptomlar görülür. Bu çalışmada, sıçanlara farklı dozlarda intravenöz (i.v.) yolla verilen grayanotoksin-III'ün doza bağımlı kardiyovasküler etkilerinin değerlendirilmesi amaçlanmıştır. Yöntem: Çalışmada, 42 Wistar albino sıçan kullanılmış ve hayvanlar Kontrol, Grup 1 (5 µg/kg), Grup 2 (10 µg/kg), Grup 3 (20 µg/kg), Grup 4 (50 µg/kg) ve Grup 5 (100 µg/kg) olmak üzere altı gruba ayrılmıştır. Elektrokardiyogram (EKG), tansiyon arteriyel ve solunum sayısı için bazal değerler elde edildikten sonra i.v. grayanotoksin uygulanmasının ardından 60 dk. boyunca bu parametreler kaydedilmiştir. Bulgular: 5 µg/kg grayanotoksin-III verilen grupta, tüm zamanlarda anlamlı bir deği-şiklik olmazken, 10 ve 20 µg/kg toksin verilen gruplarda 2. ve 5. dk.'dan sonra anlamlı biçimde solunum sayıları ve kalp tepe atım sayıları azalmış, arteryel basınçlarda düşme görülmüştür. Yirmi beşinci dk.'dan sonra ise tüm parametreler bazal değerlere yeniden geri dönmüştür. Elli ve 100 µg/kg grayanotoksin-III verilen gruplarda, 2. dk.'dan itibaren tüm parametrelerde hızla düşme olmuş ve 5-10 dk. içinde sıçanlar ölmüştür. Sonuç: Sıçanlar için i.v. grayanotoksin-III'ün 50 µg/kg ve üzerindeki yüksek dozlarda lethal olabildiği, ölümün kardiyak arrest nedeniyle görüldüğü, 5 µg/kg ve altındaki düşük dozlarda toksik etkilerin görülmediği, i.v. uygulamada toksik etkilerin yaklaşık olarak 25 dk. sürdüğü saptanmıştır. Anahtar kelimeler: Grayanotoksin-III, deli bal, kardivasküler etkiler ABSTRACTObjective: The mad honey poisonings are commonly seen in our country. The source of the toxin in mad honey is plants of Rhododendron species. Grayanotoxin-III type toxin is commonly found in these plants. Clinical effects of this toxin are bradycardia, atrioventricular block, asystole, hypotension and symptoms such as salivation. In this study; different doses of grayanotoxin-III were intravenously administered to rats (i.v) and the effect of grayanotoxin on cardiovascular system was evaluated. Methods: This study was performed on 42 Wistar albino rats and the animals were divided into six groups. Control, Group 1 (5 µg/kg), Group 2 (10 µg/kg), Group 3 (20 µg/kg), Group 4 (50 µg/kg) and Group 5 (100 µg/kg) groups were formed. Baseline values for electrocardiography (ECG), arterial blood pressure and respiratory rate were obtained and recorded for 60 minutes after administration of i.v. grayanotoxin-III. Results: Group1 (5 µg/kg) was not significantly changed in all time periods. In 10 and 20 µg/kg groups, respiratory rates, peak heart rates decreased significantly and drop in arterial blood pressures was observed after 2 nd and 5 th minutes. While 25 minutes after administration of i.v. grayanotoxin-III all parameters returned to baseline v...

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State‐dependent action of grayanotoxin I on Na⁺ channels in frog ventricular myocytes

Cited by 24 publications

References 23 publications

Distinct Sites Regulating Grayanotoxin Binding and Unbinding to D4S6 of Nav1.4 Sodium Channel as Revealed by Improved Estimation of Toxin Sensitivity

Distinct Sites Regulating Grayanotoxin Binding and Unbinding to D4S6 of Nav1.4 Sodium Channel as Revealed by Improved Estimation of Toxin Sensitivity

Pseudocholinesterase Levels Are Not Decreased in Grayanotoxin (Mad Honey) Poisoning in Most Patients

The dose-dependent cardiovascular eﬀects of intravenous grayanotoxin-III in rats

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State‐dependent action of grayanotoxin I on Na+ channels in frog ventricular myocytes

Cited by 24 publications

References 23 publications

Distinct Sites Regulating Grayanotoxin Binding and Unbinding to D4S6 of Nav1.4 Sodium Channel as Revealed by Improved Estimation of Toxin Sensitivity

Distinct Sites Regulating Grayanotoxin Binding and Unbinding to D4S6 of Nav1.4 Sodium Channel as Revealed by Improved Estimation of Toxin Sensitivity

Pseudocholinesterase Levels Are Not Decreased in Grayanotoxin (Mad Honey) Poisoning in Most Patients

The dose-dependent cardiovascular eﬀects of intravenous grayanotoxin-III in rats

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State‐dependent action of grayanotoxin I on Na⁺ channels in frog ventricular myocytes